dl-3-n-butylphthalide extends survival by attenuating glial activation in a mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease characterized by progressive muscular atrophy, paralysis and bulbar symptoms. Transgenic mice over-expressing human mutant Cu/Zn superoxide dismutase-1 (SOD1) mimicked the pathological phenotype of ALS. dl-3-n-butylphthalide (dl-NBP) has been demonstrated to play a neuroprotective role in cerebral ischemia, vascular dementia, and Alzheimer’s disease. In the current study, we examined the effect of dl-NBP in Tg (SOD1-G93A) transgenic mice, a well-studied model of ALS. Following the symptomatic onset of disease, oral administration of dl-NBP significantly improved motor performance, extended the survival interval, attenuated motor neuron loss, and delayed motor unit reduction compared to vehicle controls. These observations were further corroborated by the significant reduction in immunoreactivity of CD11b and glial fibrillary acidic protein (GFAP), markers for microglia and astrocytes, respectively. Additionally, downregulation of nuclear factor κB (NF-κB) p65 and tumor necrosis factor-α (TNF-α) protein levels and a slight upregulation of NF-E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were found in the spinal cord of Tg (SOD1-G93A) mice treated by dl-NBP. These results suggest that dl-NBP might be a promising compound in the treatment of ALS.This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’.

► dl-NBP improved motor performance and extended the survival interval.
► dl-NBP attenuated motor neuron loss and delayed motor unit reduction.
► dl-NBP reduced glial activations.
► dl-NBP upregulated the expression of Nrf2, suppressed the NF-κB p65 and TNF-α levels.